Pro-inflammatory cytokines have potent effects in the brain on altering behavioral and endocrine responses. Elevated levels of proinflammatory cytokines mediate many of the behavioral and endocrine responses observed following a variety of stimuli including peripheral immune challenge, exposure to some physical/psychological stressors, brain injury, and central inflammatory conditions such as Alzheimer's, Parkinson's, and multiple sclerosis. While the biological effects of elevated brain cytokines have been well characterized, the mechanisms that regulate brain cytokine production remain largely unknown. The aims of this proposal are to examine the mechanisms that regulate both the induction and inhibition of brain cytokines following a peripheral immune challenge, and establish the physiological importance of this regulation on various behavioral and endocrine responses such as fever, decreased food/water intake, impaired earning/memory, and activation of the hypothalamus-pituitary-adrenal (HPA) axis. Recent data from our laboratory demonstrate that [unreadable]-adrenoceptors play an important role in the induction of brain cytokines, and that central administration of a [unreadable]-adrenoceptor antagonist blocks or attenuates cytokine production following a peripheral Escherichia coli (E. coli) challenge in distinct brain areas. Interestingly, [unreadable]-adrenoceptors only mediate brain cytokine production in brain areas innervated by noradrenergic neurons located in the nucleus of the solitary tract (NTS), and not in brain areas largely innervated by noradrenergic neurons located in the locus coeruleus (LC). These data support previously published work demonstrating that following immune stimuli, NTS neurons are rapidly and robustly activated, while only a subpopulation of LC neurons become activated. Furthermore, we propose that activation of LC neurons during an immune response function to inhibit NTS activity. This hypothesis is supported by observations that demonstrate stimulation of LC neurons suppresses NTS activity, and our preliminary data that lesions of LC projections results in exaggerated cytokine production following E. coli challenge in NTS projection sites. These data lead to our current hypothesis to be tested in this proposal that during an immune challenge activation of noradrenergic neurons in the NTS induce cytokine production in discrete brain areas via activation of [unreadable]-adrenoceptors, while activation of LC neurons during an immune response serve to inhibit NTS activity. [unreadable] [unreadable] [unreadable]